EP3288941B1 - Spiro-isochinolin-3,4'-piperidin-verbindungen mit aktivität gegen schmerzen - Google Patents

Spiro-isochinolin-3,4'-piperidin-verbindungen mit aktivität gegen schmerzen Download PDF

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EP3288941B1
EP3288941B1 EP16719214.5A EP16719214A EP3288941B1 EP 3288941 B1 EP3288941 B1 EP 3288941B1 EP 16719214 A EP16719214 A EP 16719214A EP 3288941 B1 EP3288941 B1 EP 3288941B1
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unsubstituted
substituted
alkyl
hydrogen
compound
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EP3288941A1 (de
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Carmen ALMANSA-ROSALES
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Esteve Pharmaceuticals SA
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Esteve Pharmaceuticals SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to new spiro-isoquinoline-3,4'-piperidine compounds having a great affinity for sigma receptors, especially sigma-1 ( ⁇ 1 ) receptors, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments.
  • sigma receptors include cell surface receptors of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids.
  • CNS central nervous system
  • sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease ( Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355 ).
  • the sigma receptor/s as used in this application is/are well known and defined using the following citation: This binding site represents a typical protein different from opioid, NMDA, dopaminergic, and other known neurotransmitter or hormone receptor families ( G. Ronsisvalle et al. Pure Appl. Chem. 73, 1499-1509 (2001 )).
  • the sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs.
  • (+)SKF-10047 has nanomolar affinity for the sigma-1 ( ⁇ 1 ) site, and has micromolar affinity for the sigma-2 ( ⁇ 2 ) site.
  • Haloperidol has similar affinities for both subtypes.
  • the ⁇ 1 receptor is a non-opiaceous type receptor expressed in numerous adult mammal tissues (e.g. central nervous system, ovary, testicle, placenta, adrenal gland, spleen, liver, kidney, gastrointestinal tract) as well as in embryo development from its earliest stages, and is apparently involved in a large number of physiological functions. Its high affinity for various pharmaceuticals has been described, such as for (+)SKF-10047, (+)-pentazocine, haloperidol and rimcazole, among others, known ligands with analgesic, anxiolytic, antidepressive, antiamnesic, antipsychotic and neuroprotective activity.
  • ⁇ 1 receptor is of great interest in pharmacology in view of its possible physiological role in processes related to analgesia, anxiety, addiction, amnesia, depression, schizophrenia, stress, neuroprotection and psychosis [ Kaiser et al (1991) Neurotransmissions 7 (1): 1-5 ], [ Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355 ] and [ Bowen W.D. (2000) Pharmaceutica Acta Helvetiae 74: 211-218 ].
  • the ⁇ 2 receptor is also expressed in numerous adult mammal tissues (e.g. nervous system, immune system, endocrine system, liver, kidney).
  • ⁇ 2 receptors can be components in a new apoptosis route that may play an important role in regulating cell proliferation or in cell development. This route seems to consist of ⁇ 2 receptors joined to intracellular membranes, located in organelles storing calcium, such as the endoplasmic reticulum and mitochondria, which also have the ability to release calcium from these organelles.
  • the calcium signals can be used in the signaling route for normal cells and/or in induction of apoptosis.
  • Agonists of ⁇ 2 receptors induce changes in cell morphology, apoptosis in several types of cell lines and regulate the expression of p-glycoprotein mRNA, so that they are potentially useful as antineoplasic agents for treatment of cancer.
  • ⁇ 2 receptor agonists have been observed to induce apoptosis in mammary tumour cell lines resistant to common antineoplasic agents that damage DNA.
  • agonists of ⁇ 2 receptors enhance the cytotoxic effects of these antineoplasic agents at concentrations in which the agonist is not cytotoxic.
  • agonists of ⁇ 2 receptors can be used as antineoplasic agents at doses inducing apoptosis or at sub-toxic doses in combination with other antineoplasic agents to revert the resistance to the drug, thereby allowing using lower doses of the antineoplasic agent and considerably reducing its adverse effects.
  • Antagonists of ⁇ 2 receptors can prevent the irreversible motor side effects caused by typical neuroleptic agents.
  • antagonists of ⁇ 2 receptors can be useful as agents for improving the weakening effects of delayed dyskinesia appearing in patients due to chronic treatment of psychosis with typical antipsychotic drugs, such as haloperidol.
  • ⁇ 2 receptors also seem to play a role in certain degenerative disorders in which blocking these receptors could be useful.
  • Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them.
  • Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition ( Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86 ).
  • Most studies have implied that sigma binding sites (receptors) are plasmalemmal elements of the signal transduction cascade.
  • Drugs reported to be selective sigma ligands have been evaluated as antipsychotics ( Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077 ).
  • the existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
  • Spiro[benzopyran] or spiro[benzofuran] derivatives were also disclosed in EP1847542 as well as pyrazole derivatives ( EP1634873 ) with pharmacological activity on sigma receptors.
  • WO2009/071657 discloses some tricyclic triazolic compounds although structurally different to the ones of the current invention with activity towards sigma receptors.
  • the present invention discloses novel compounds with great affinity to sigma receptors and having high solubility in a physiological media which might be used for the treatment of sigma related disorders or diseases.
  • K i which is preferably ⁇ 1000 nM, more preferably ⁇ 500 nM, even more preferably ⁇ 100 nM.
  • the invention is directed in a main aspect to a compound of general Formula (I), wherein R 1 , R 2 , R 3 , R 3' , R 3" , R 3"' , R 4 , R 4' , R 5 , R 5' , X, m, n and p are as defined below in the detailed description.
  • a further object of the invention refers to the processes for preparation of compounds of general formula (I).
  • a still further object of the invention refers to the use of intermediate compounds for the preparation of a compound of general formula (I).
  • the invention is directed to a family of structurally distinct spiro-isoquinoline-3,4'-piperidine derivatives which have a pharmacological activity towards the sigma ( ⁇ ) receptor, thus solving the above problem.
  • the present invention is directed to compounds of general Formula (I): wherein
  • These compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the aryl in R 2 is not substituted with - NR 12 S(O) 2 R 12' .
  • the compound according to the invention of general Formula (I) is a compound of general Formula (I') wherein R 1 , R 2 , R 4 , R 4' and n are as defined in the description.
  • the compound according to the invention of general Formula (I) is a compound of general Formula (I 2 ') wherein R 1 , R 2 and n are as defined in the description.
  • the compound according to the invention of general Formula (I) is a compound of general Formula (I 3 ') wherein R 1 , R 2 and n are as defined in the description.
  • the compound according to the invention of general Formula (I) is a compound of general Formula (I 4 ') wherein R 1 , R 2 , R 3 , R 3' , R 3" , R 3"' , R 4 , R 4' , R 5 , R 5' , m, n and X are as defined in the description.
  • p', R 5" and R 5"' are added. These are reflecting the statements below in the definitions of substituitions on alkyl etc. or aryl etc. that "when different radicals R 1 to R 13"' and R x are present simultaneously in Formula I they may be identical or different". Thus this is reflecting that R 5" and R 5"' are or could be different from R 5 and R 5' or not and - accordingly - p' being 0 or 1, 2 or 3 is naturally resulting from p being 1, 2, 3 or 4.
  • R 2 is still present in general Markush Formulae (I), (I'), (I 2 '), (I 3 ') or (I 4 ').
  • alkyl is understood as meaning saturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses e.g. -CH 3 and -CH 2 -CH 3 .
  • C 1-2 -alkyl represents C1- or C2-alkyl
  • C 1-3 -alkyl represents C1-, C2- or C3-alkyl
  • C 1-4 -alkyl represents C1-, C2-, C3- or C4-alkyl
  • C 1-5 -alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl
  • C 1-6 -alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • C 1-7 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C 1-10 -alkyl represents C1-, C2-, C3-, C4-, C5-, C
  • the alkyl radicals are preferably methyl, ethyl, propyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, if substituted also CHF 2 , CF 3 or CH 2 OH etc.
  • alkyl is understood in the context of this invention as C 1-8 alkyl like methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; preferably is C 1-6 alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more preferably is C 1-4 alkyl like methyl, ethyl, propyl or butyl.
  • the alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl).
  • alkenyl is C 2-10 -alkenyl or C 2-8 -alkenyl like ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene; or is C 2-6 -alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C 2-4 -alkenyl, like ethylene, propylene, or butylenes.
  • Alkynyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -C ⁇ C-CH 3 (1-propinyl).
  • alkynyl in the context of this invention is C 2-10 -alkynyl or C 2-8 -alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, or octyne; or is C 2-6 -alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C 2-4 -alkynyl like ethyne, propyne, butyene, pentyne, or hexyne.
  • alkyl also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl
  • substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen (F, CI, Br, I), -NR c R c"' , - SR c , -S(O)R c , -S(O) 2 R c , -OR c , -C(O)OR c , -CN, -C(O)NR c R c' , haloalkyl, haloalkoxy or -OC 1-4 alkyl being unsubstituted or substituted by one or more of -OR c or halogen (F, Cl, I, Br), being R c represented by R 11 , R 12 , R 10 , (being R c represented by
  • alkyl also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl
  • alkenyl, alkynyl or O-alkyl substituted is understood in the context of this invention that any alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl which is substituted is substituted with one or more of halogen (F, CI, Br, I), -OR c , -CN, -SR c ,-S(O)R c , and - S(O) 2 R c , haloalkyl, haloalkoxy or -OC 1-4 alkyl being unsubstituted or substituted by one or more of -OR c or halogen (F, CI, I, Br), being R c represented by R 11 , R 12 , R 10 , (being R c represented by R 11
  • More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents.
  • This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF 3 , or at different places of the same molecule, as in the case of e.g. - CH(OH)-CH CH-CHCl 2 .
  • haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, CI, Br, I). It encompasses e.g. -CH 2 Cl, -CH 2 F, -CHCl 2 , -CHF 2 , -CCl 3 , -CF 3 and - CH 2 -CHCl 2 .
  • haloalkyl is understood in the context of this invention as halogen-substituted C 1-4 -alkyl representing halogen substituted C1-, C2-, C3- or C4-alkyl.
  • the halogen-substituted alkyl radicals are thus preferably methyl, ethyl, propyl, and butyl.
  • Preferred examples include -CH 2 Cl, -CH 2 F, - CHCl 2 , -CHF 2 , and -CF 3 .
  • haloalkoxy is understood as meaning an -O-alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -OCH 2 Cl, -OCH 2 F, -OCHCl 2 , -OCHF 2 , - OCCl 3 , -OCF 3 and -OCH 2 -CHCl 2 .
  • haloalkyl is understood in the context of this invention as halogen-substituted -OC 1-4 -alkyl representing halogen substituted C1-, C2-, C3- or C4-alkoxy.
  • the halogen-substituted alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and O-butyl.
  • Preferred examples include -OCH 2 Cl, -OCH 2 F, -OCHCl 2 , -OCHF 2 , and - OCF 3 .
  • cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted.
  • C 3-4 -cycloalkyl represents C3- or C4-cycloalkyl
  • C 3-5 -cycloalkyl represents C3-, C4- or C5-cycloalkyl
  • C 3-6 -cycloalkyl represents C3-, C4-, C5-or C6-cycloalkyl
  • C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3-6 -cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl represents C4- or C5-cycloalkyl
  • Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantly.
  • cycloalkyl is C 3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C 3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C 3-6 -cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.
  • Aryl is understood as meaning 5 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphtyl or anthracenyl, preferably is phenyl.
  • a heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 5 to 18 membered mono or polycyclic heterocyclic ring systems, with at least one saturated or unsaturated ring which contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring.
  • a heterocyclic group can also be substituted once or several times.
  • Examples include non-aromatic heterocyclyls such as tetrahydropyrane, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazole, benzothiazole, indole, benzotriazole, carbazole and quinazoline.
  • non-aromatic heterocyclyls such as tetrahydropyrane, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazo
  • heterocyclyls as understood herein include heteroaryls and non-aromatic heterocyclyls.
  • heterocyclyl is defined as a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring.
  • it is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring.
  • heterocyclyls include oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, , benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyr
  • oxopyrrolidine is understood as meaning pyrrolidin-2-one.
  • the ring system is defined first as an aromatic heterocyclyl (heteroaryl) if at least one aromatic ring contains a heteroatom. If no aromatic ring contains a heteroatom, then the ring system is defined as a non-aromatic heterocyclyl if at least one non-aromatic ring contains a heteroatom. If no non-aromatic ring contains a heteroatom, then the ring system is defined as an aryl if it contains at least one aryl cycle. If no aryl is present, then the ring system is defined as a cycloalkyl if at least one non-aromatic cyclic hydrocarbon is present.
  • alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through a C 1-6 -alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times.
  • alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH 2 -) groups.
  • alkylaryl is benzyl (i.e. -CH 2 -phenyl).
  • alkylheterocyclyl is understood as meaning an heterocyclyl group being connected to another atom through a C 1-6 -alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times.
  • alkylheterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (-CH 2 -) groups.
  • alkylheterocyclyl is -CH 2 -pyridine.
  • alkylcycloalkyl is understood as meaning an cycloalkyl group being connected to another atom through a C 1-6 -alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times.
  • alkylcycloalkyl is understood as meaning an cycloalkyl group (see above) being connected to another atom through 1 to 4 (-CH 2 -) groups.
  • alkylcycloalkyl is -CH 2 -cyclopropyl.
  • the aryl is a monocyclic aryl. More preferably the aryl is a 5, 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 5 or 6 membered monocyclic aryl.
  • the heteroaryl is a monocyclic heteroaryl. More preferably the heteroaryl is a 5, 6 or 7 membered monocyclic heteroaryl. Even more preferably the heteroaryl is a 5 or 6 membered monocyclic heteroaryl.
  • the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl.
  • the cycloalkyl is a monocyclic cycloalkyl. More preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3, 4, 5 or 6 membered monocyclic cycloalkyl.
  • aryl including alkyl-aryl
  • cycloalkyl including alkyl-cycloalkyl
  • heterocyclyl including alkyl-heterocyclyl
  • aryl including alkyl-aryl
  • cycloalkyl including alkyl-cycloalkyl
  • heterocyclyl including alkyl-heterocyclyl
  • any aryl, cycloalkyl and heterocyclyl which is substituted is substituted (also in an alyklaryl, alkylcycloalkyl or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I), -R c , -OR c , -CN , -NO 2 , -NR c R c"' , NR c C(O)R c' , -NR c S(O) 2 R c' , - S(O) 2 NR c R c' , -NR c C(O)NR c' -R c" , haloalkyl, haloalkoxy, -
  • cycloalkyl including alkyl-cycloalkyl
  • heterocycly including alkylheterocyclyl
  • non-aromatic heterocyclyl including non-aromatic alkyl-heterocyclyl
  • a ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with "joined" meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.
  • leaving group means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-) or mesylate.
  • salt is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • a counter-ion a cation or anion
  • complexes of the active compound with other molecules and ions in particular complexes via ionic interactions.
  • physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
  • physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH 4 , but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
  • Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals.
  • the salt formed with a physiologically tolerated acid that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • the compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.
  • solvate any compound that is a solvate of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates.
  • the term "solvate" according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery” Taylor & Francis (April 2002).
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon or of a nitrogen by 15 N-enriched nitrogen are within the scope of this invention.
  • the compounds of formula (I) as well as their salts or solvates of the compounds are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts. This applies also to its solvates or prodrugs.
  • the compound according to the invention of general Formula (I) is a compound wherein
  • These preferred compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein m is 0, 1, 2, 3, 4, 5 or 6; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 0, 1, 2, 3 or 4; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general f Formula (I) is a compound wherein p is 1, 2, 3 or 4; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein X is selected from a bond, -C(R x R x' )- and -C(R x )(OR 7 )-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein X is selected from a bond and -C(R x R x' )-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, -C(O)R 6 , -C(O)OR 6 , -C(O)NR 6 R 6' and -S(O) 2 R 6 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 1 is selected from hydrogen, substituted or unsubstitute
  • the compound according to the invention of general Formula (I) is a compound wherein R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and -C(O)R 6 ,; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and -C(O)R 6 ,; optionally in form of one
  • the compound according to the invention of general Formula (I) is a compound wherein R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl and - C(O)R 6 ,; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 2 is selected from substituted or unsubstituted aryl; preferably substituted or unsubstituted phenyl, more preferably unsubstituted phenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 2 is substituted or unsubstituted heterocyclyl, preferably substituted or unsubstituted morpholine, more preferably unsubstituted morpholine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 3 is selected from hydrogen, halogen, -R 9 , -OR 9 , -NO 2 , -NR 9 R 9"' , - NR 9 C(O)R 9' , -NC(O)OR 9 , -NR 9 S(O) 2 R 9' , -S(O) 2 NR 9 R 9' , -NR 9 C(O)NR 9' R 9" , -SR 9 , -S(O)R 9 , -S(O) 2 R 9 , -CN, haloalkyl, haloalkoxy, -C(O)OR 9 , -C(O)NR 9 R 9' , - NR 9 S(O) 2 NR 9' R 9" and -OC(O)R 9 ; R 3' , R 3" and R 3"' are independently selected from hydrogen, halogen, -R 9 , -OR 9 , -NO 2 , -NR 9 R 9"'
  • R 3 is selected from hydrogen, halogen, -R 9 , -OR 9 , -NO 2 , -NR 9 R 9"' , - NR 9 C(O)R 9' , -NC(O)OR 9 , -NR 9 S(O) 2 R 9' , -S(O) 2 NR 9 R 9' , -NR 9 C(O)NR 9' R 9" , -SR 9 , -S(O)R 9 , -S(O) 2 R 9 , -CN, haloalkyl, haloalkoxy, -C(O)OR 9 , -C(O)NR 9 R 9' , - NR 9 S(O) 2 NR 9' R 9" and -OC(O)R 9 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereo
  • R 3' , R 3" and R 3"' are independently selected from hydrogen, halogen, -R 9 , - NO 2 , -NR 9 R 9"' , -NR 9 C(O)R 9' , -NC(O)OR 9 , -NR 9 S(O) 2 R 9' , -S(O) 2 NR 9 R 9' , - NR 9 C(O)NR 9' R 9" , -SR 9 , -S(O)R 9 , -S(O) 2 R 9 , -CN, haloalkyl, haloalkoxy, - C(O)OR 9 , -C(O)NR 9 R 9' , -NR 9 S(O) 2 NR 9' R 9" and -OC(O)R 9 ; optionally in form of one of the stereoisomers, preferably enantiomers
  • R 3 is selected from hydrogen, halogen, -Rg, -OR 9 , and -NR 9 R 9"' ;
  • R 3' , R 3" and R 3"' are independently selected from hydrogen, halogen, -R 9 , and - NR 9 R 9"' ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 3 is selected from hydrogen, halogen, -Rg, -OR 9 , and -NR 9 R 9"' ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 3' , R 3" and R 3"' are independently selected from hydrogen, halogen, -R 9 , and - NR 9 R 9"' ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 4 is selected from hydrogen, -OR 8 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C(O)OR 8 , -C(O)NR 8 R 8' , -NR 8 C(O)R 8' , -NR 8 R 8"' and -NC(O)OR 8 ;
  • R 4' is selected from hydrogen, or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably
  • R 4 is selected from hydrogen, -OR 8 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C(O)OR 8 , -C(O)NR 8 R 8' , -NR 8 C(O)R 8' , -NR 8 R 8"' and -NC(O)OR 8 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 4' is selected from hydrogen, or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 5 and R 5' are independently selected from hydrogen, or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 6 and R 6' are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl , substituted or unsubstituted aryl or substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted alkylcycloalkyl, and substituted or unsubstituted heterocyclyl or substituted or unsubstituted alkyheterocylcyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or
  • R 7 , R 7' and R 7" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 7"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 8 , R 8' and R 8" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 8"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 9 , R 9' and R 9" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 9"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 10 , and R 10' are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 11 , R 11' and R 11" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 11"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 12 , R 12' and R 12" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, and unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 12"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 13 , R 13' and R 13" are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, unsubstituted aryl, unsubstituted alkylaryl, unsubstituted cycloalkyl and unsubstituted alkylcycloalkyl, unsubstituted heterocyclyl and unsubstituted alkyheterocylcyl ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 13"' is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R x is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C(O)OR 7 , -C(O)NR 7 R 7' , -NR 7 C(O)R 7' , and -NR 7 R 7"' ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R x' is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein X is a bond; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein X is -C(R x R x' )-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein X is -CH 2 -; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein m is 0 or 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • n is 0 or 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein p is 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the according to the invention of general Formula (I) is a compound wherein m is 0 or 1, n is 0 or 1 and p is 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or -C(O)R 6 ; and wherein R 6 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 3 is selected from hydrogen, halogen, -R 9 , -OR 9 , and -NR 9 R 9"' ; and R 3' , R 3" and R 3"' are independently selected from hydrogen, halogen, -R 9 , and-NR 9 R 9"' ;
  • R 4 is selected from hydrogen, -OR 8 , substituted or unsubstituted C 1-6 alkyl; R 4' is selected from hydrogen, or substituted or unsubstituted C 1-6 alkyl; and wherein R 8 is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the according to the invention of general Formula (I) is a compound wherein X is a bond; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, p is 1, X is a bond, and R 2 is substituted or unsubstituted phenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, p is 1, X is a bond, and R 2 is substituted or unsubstituted morpholine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 0, p is 1, X is a bond, and R 2 is substituted or unsubstituted phenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond and R 1 is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted acetyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 0, m is 0, p is 1, X is a bond and R 1 is hydrogen or substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond, and R 1 is -C(O)R 6 , wherein R 6 is substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond, R 1 is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted acetyl and R 2 is substituted or unsubstituted phenyl or substituted or unsubstituted morpholine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 4 and R 4' are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound is a compound, wherein in R 1 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 2 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R x as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R x' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 3 as defined in any of the embodiments of the present invention, the C 1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the C 1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in
  • the compound is a compound, wherein in R 3' , R 3" and R 3"' as defined in any of the embodiments of the present invention, the C 1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the C 1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or di
  • the compound is a compound, wherein in R 4 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 4' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 5 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 5' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 6 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 6' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 7 , R 7' and R 7" as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 7"' as defined in any of the embodiments of the present invention,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound is a compound, wherein in R 8 , R 8' and R 8" , as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 8"' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 9 , R 9' and R 9" as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 9"' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 10 as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 10' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 11 , R 11' and R 11" as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 11"' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 12 , R 12 , and R 12" as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 12"' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 13 , R 13' and R 13" as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein in R 13''' as defined in any of the embodiments of the present invention,
  • the compound is a compound, wherein n is 0, 1, 2, 3 or 4, preferably n is 0 or 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound is a compound, wherein m is 0, 1, 2, 3, 4, 5 or 6; preferably m is 0 or 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound is a compound, wherein p is 1, 2, 3 or 4; preferably p is 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound is a compound, wherein X is selected from a bond, and -C(R x R x' )-; preferably X is a bond; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 1 is hydrogen or a substituted or unsubstituted group selected from methyl and acetyl.
  • R 1 is hydrogen or a substituted or unsubstituted methyl.
  • R 2 is a substituted or unsubstituted phenyl or morpholine.
  • R 2 is a substituted or unsubstituted phenyl.
  • R 3 is hydrogen
  • R 3' , R 3'' and R 3''' are all hydrogen.
  • R 3 , R 3' , R 3'' and R 3''' are all hydrogen.
  • R 4 and R 4' are both hydrogen.
  • R 5 and R 5' are both hydrogen.
  • R 6 is substituted or unsubstituted methyl, preferably unsubstituted methyl.
  • R x is hydrogen
  • R x ' is hydrogen
  • R x and R x ' are both hydrogen.
  • n 0 or 1.
  • m is 0 or 1.
  • p is 1.
  • X is a bond or -CH 2 -.
  • X is a bond
  • the halogen is fluorine, chlorine, iodine or bromine.
  • halogen is fluorine or chlorine.
  • the compounds of the general Formula (I) are selected from EX Chemical name 1 1'-phenethyl-2,4-dihydro-1H-spiro[isoquinoline-3,4'-piperidin]-1-one 2 1'-benzyl-2,4-dihydro-1H-spiro[isoquinoline-3,4'-piperidin]-1-one 3 1'-phenethyl-2,4-dihydro-1H-spiro[isoquinoline-3,4'-piperidine] 4 1'-benzyl-2,4-dihydro-1H-spiro[isoquinoline-3,4'-piperidine] 5 1-(1'-phenethyl-1H-spiro[isoquinoline-3,4'-piperidine]-2(4H)-yl)ethanone 6 1'-benzyl-2-methyl-2,4-dihydro-1H-spiro[isoquinoline-3,4'-piperidine] 7
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, p is 1, X is a bond, and R 2 is substituted or unsubstituted phenyl; the compound being exemplified in examples 1, 3 and 5; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, p is 1, X is a bond, and R 2 is substituted or unsubstituted morpholine; the compound being exemplified in examples 7; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 0, p is 1, X is a bond, and R 2 is substituted or unsubstituted phenyl; the compound being exemplified in examples 2, 4 and 6; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond and R 1 is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted acetyl; the compound being exemplified in examples 1, 3, 5 and 7; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 0, m is 0, p is 1, X is a bond and R 1 is hydrogen or substituted or unsubstituted methyl; the compound being exemplified in examples 2, 4 and 6; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond, and R 1 is -C(O)R 6 , wherein R 6 is substituted or unsubstituted methyl; the compound being exemplified in examples 5; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein n is 1, m is 0, p is 1, X is a bond, R 1 is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted acetyl and R 2 is substituted or unsubstituted phenyl or substituted or unsubstituted morpholine; the compound being exemplified in examples 1, 3, 5 and 7; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein R 4 and R 4' are both hydrogen, the compound being exemplified in examples 3 to 7; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, -C(O)R 6 , -C(O)OR 6 , -C(O)NR 6 R 6' and -S(O) 2 R 6 ;
  • R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • the cycloalkyl, aryl or heterocyclyl in R 1 if substituted, is substituted with one or more substituent/s selected from halogen, -R 11 , -OR 11 , -NO 2 ,-NR 11 R 11''' , NR 11 C(O)R 11' , -NR 11 S(O) 2 R 11' , -S(O) 2 NR 11 R 11' ,-NR 11 C(O)NR 11' R 11'' -SR 11 , -S(O)R 11 , S(O) 2 R 11 , -CN, haloalkyl, haloalkoxy, -C(O)OR 11 , -C(O)NR 11 R 11' , - and -NR 11 S(O) 2 NR 11' H 11'' ; optionally in form of one
  • the cycloalkyl, aryl or heterocyclyl in R 6 is substituted with one or more substituent/s selected from halogen, -R 11 , -OR 11 , -NO 2 , -NR 11 R 11''' , NR 11 C(O)R 11' ,-NR 11 S(O) 2 R 11' -S(O) 2 NR 11 R 11' -NR 11 C(O)NR 11' H 11'' , -SR 11 , -S(O)R 11 , S(O) 2 R 11 , -CN, haloalkyl, haloalkoxy, -C(O)OR 11 , -C(O)NR 11 R 11' , - and
  • the cycloalkyl, aryl or heterocyclyl in R 2 if substituted, is substituted with one or more substituent/s selected from halogen, -R 12 , -OR 12 , -NO 2 , -NR 12 R 12''' , NR 12 C(O)R 12' , -S(O) 2 NR 12 R 12' -NR 12 C(O)NR 12' R 12'' , -SR 12 , -S(O)R 12 , S(O) 2 R 12 , -CN, haloalkyl, haloalkoxy, -C(O)OR 12 , -C(O)NR 12 R 12' , and-NR 12 S(O) 2 NR 12' R 12'' ; optionally in form of one of the stereoisomers, preferably enantiomers or
  • the alkyl, alkenyl or alkynyl, other than those defined in R 1 , R 2 or R 6 is substituted with one or more substituent/s selected from -OR 10 , halogen, -CN, haloalkyl, haloalkoxy, -SR 10 , -S(O)R 10 , and -S(O) 2 R 10 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the aryl, heterocyclyl or cycloalkyl also in alkylaryl, alkylcycloalkyl and alkylheterocyclyl, other than those defined in R 1 , R 2 or R 6 , if substituted, is substituted with one or more substituent/s selected from halogen, -R 13 , -OR 13 , -NO 2 , -NR 13 R 13''' , NR 13 C(O)R 13' , -NR 13 S(O) 2 R 13' , -S(O) 2 NR 13 R 13' ,-NR 13 C(O)NR 13' R 13' , -SR 13 , -S(O)R 13 , S(O) 2 R 13 ,
  • the halogen is fluorine, chlorine, iodine or bromine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the halogen is fluorine or chlorine optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the haloalkyl is -CF3 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the haloalkoxy is -OCF3; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the ⁇ 1 receptor it is a very preferred embodiment in which the compounds are selected which act as ligands of the ⁇ 1 receptor and especially compounds which have a binding expressed as K i which is preferably ⁇ 1000 nM, more preferably ⁇ 500 nM, even more preferably ⁇ 100 nM.
  • the compounds of the invention represented by the above described Formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E).
  • the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • a preferred aspect of the invention is also a process for the production of a compound according to Formula (I), following scheme 1.
  • a preferred embodiment of the invention is a process for the production of a compound according to Formula (I), wherein m, n, p, R 1 , R 2 , R 3 , R 3' , R 3'' , R 3''' R 4 , R 4' , R 5 , R 5' and X have the meanings defined in the description.
  • a process for the production of a compound according to Formula (I) comprises reacting a compound of Formula (Ib') with a compound of Formula (XIa) in an alkylating reaction, (XIb) in a reductive amination reaction, (XIc) in an acylation reaction or (XId) in an acylation reaction following the operative conditions as described in STEP 7 of scheme 1, wherein L, W, m, n, p, R 1 , R 2 , R 3 , R 3' , R 3'' , R 3'' , R 4 , R 4' , R 5 , R 5' , R 6 and X have the meaning as defined in the description and in scheme 1.
  • the production of a compound according to Formula (I), wherein R 4 and R 4' are hydrogen comprises reacting a compound of Formula (Ib) with a compound of Formula (XIa) in an alkylating reaction, (XIb) in a reductive amination reaction, (XIc) in an acylation reaction or (XId) in an acylation reaction or following the operative conditions as described in STEP 7 of scheme 1, wherein L, W, m, n, p, R 1 , R 2 , R 3 , R 3' , R 3'' , R 3''' , R 5 , R 5' , R 6 and X have the meaning as defined in the description and in scheme 1.
  • a process for the production of a compound according to Formula (X') or (Ic') comprises reacting a compound of Formula (IX') or (Ib') with a compound of Formula (XIa) in an alkylating reaction, (XIb) in a reductive amination reaction, (XIc) in an acylation reaction or (XId) in an acylation reaction following the operative conditions as described in STEP 7 of scheme 1, wherein PG, Y, L, W, m, R 1 , R 3 , R 3' , R 3'' , R 3' , R 4 , R 4' and R 6 have the meaning as defined in the description and in scheme 1.
  • a process for the production of a compound according to Formula (I) comprises reacting a compound of Formula (XVII') with a compound of Formula (XIIIa) in an alkylation reaction or (XIIIb) in a reductive amination reaction following the operative conditions as described in the general part of scheme 1, wherein L, m, n, p, R 1 , R 2 , R 3 , R 3' , R 3'' , R 3''' R 4 , R 4' , R 5 , R 5' and X have the meaning as defined in the description and in scheme 1.
  • a process for the production of a compound according to Formula (X) or (Ic) comprises reacting a compound of Formula (IX) or (Ib) respectively, with a compound of Formula (XIa) in an alkylating reaction, (XIb) in a reductive amination reaction, (XIc) in an acylation reaction or (XId) in an acylation reaction following the operative conditions as described in STEP 7 of scheme 1, wherein PG, Y, L, W, m, R 1 , R 3 , R 3' , R 3'' , R 3'' and R 6 have the meaning as defined in the description and in scheme 1.
  • a process for the production of a compound according to Formula (VIIa) or (VIIb) comprises reacting a compound of Formula (VIa) or (VIb) respectively, with hydroxylamine following the operative conditions as described in STEP 4 of scheme 1, wherein PG, Y, R 3 , R 3' , R 3'' and R 3''' have the meaning as defined in the description and in scheme 1.
  • a process for the production of a compound according to Formula (IVa) or (IVb) comprises reacting a compound of Formula (IIa) or (IIb) respectively, with a compound of Formula (III) following the operative conditions as described in STEP 1 of scheme 1, wherein PG, Y, L, R 3 , R 3' , R 3'' and R 3''' have the meaning as defined above in the description and in scheme 1.
  • a compound of Formula (IIa) or (IIb), wherein PG and Y have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (III), wherein L, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (IVa) or (IVb), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (Va) or (Vb), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (VIa) or (VIb), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (VIIa) or (VIIb), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (VIII) or (la), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (IX) or (Ib), wherein PG, Y, R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (X) or (Ic), wherein m, PG, Y, R 1 , R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (XIa), wherein m, L and R 1 have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (XII), wherein R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (XVI), wherein R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • a compound of Formula (XVII), wherein m, R 1 , R 3 , R 3' , R 3'' and R 3'' have the meaning as defined above in the description and in scheme 1, is used for the preparation of compounds of Formula (I).
  • reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography.
  • these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
  • Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to general formula I or a pharmaceutically acceptable salt or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • the pharmaceutical compositions are in oral form, either solid or liquid.
  • Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form.
  • Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
  • Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
  • an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament.
  • Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament for the treatment of a sigma-1 ( ⁇ 1 ) receptors related disease.
  • Another aspect of the invention refers to a compound of the invention according as described above according to general formula I, or a pharmaceutically acceptable salt or isomer thereof, for use as a medicament for the treatment of pain.
  • the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.
  • Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain.
  • the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.
  • Another aspect of this disclosure relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a compound as above defined or a pharmaceutical composition thereof are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.
  • L is a leaving group such as chloro, bromo, mesylate or toxylate and W is chloro, bromo, -OH, -O-methyl (-OMe) or -O-ethyl (-OEt), Y is the group indicated in Scheme 1 and PG is a protecting group.
  • the reductive amination of a compound of formula IX or Ib with a compound of formula XIb is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in a suitable solvent, preferably methanol, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at room temperature.
  • a reductive reagent preferably sodium triacetoxyborohydride
  • a suitable solvent preferably methanol
  • the acylation reaction of a compound of formula IX or Ib with a compound of formula XIc or XId can be effected in different conditions depending on the acid reagent nature.
  • the reaction is carried out with an acid anhydride XId, in the presence of a suitable solvent, such as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide, preferably in dichloromethane; in the presence of an organic base such as triethylamine, pyridine or diisopropylethylamine, preferably pyridine; at a suitable temperature comprised between room temperature and the reflux temperature, preferably at reflux temperature.
  • a suitable solvent such as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide, preferably in dichloromethane
  • an organic base such as triethylamine, pyridine or diisopropylethylamine, preferably pyridine
  • Steps 1 to 7 represents the general route for the preparation of compounds of formula I. Additionally, the functional groups present in any of the positions can be interconverted using reactions known to those skilled in the art.
  • the protecting groups of the different intermediates can be deprotected at any step and subsequently substituted to provide variations in the group P.
  • compounds VIII can be deprotected to provide compounds XII, compounds IX to provide compounds XVI and compounds X to provide compounds XVII.
  • the protecting group is benzyl the deprotection is carried out with hydrogen at a pressure comprised between 1 and 10 bar, in a suitable solvent such as methanol or ethanol, optionally in the presence of an acid such as acetic or hydrochloric acid, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at room temperature.
  • the unprotected derivatives XVI can also be obtained by reduction of intermediates XII using the same conditions described above for the reduction of VIII.
  • compounds of general formula la,b,c can be respectively prepared by reaction with suitable reagents, such as those of formula XIIIa-b, using different conditions depending on the reagent nature.
  • the alkylation reaction with a compound of formula XIIIa is carried out in a suitable solvent, such as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide, preferably in acetonitrile; in the presence of an inorganic base such as K 2 CO 3 or Cs 2 CO 3 , or an organic base such as triethylamine or diisopropylethylamine, preferably K 2 CO 3 ; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, this reaction can be carried out in a microwave reactor. Additionally, an activating agent such as NaI can be used.
  • a suitable solvent such as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide, preferably in acetonitrile
  • an inorganic base such as K 2 CO 3 or Cs 2 CO 3
  • an organic base such as triethylamine or diisopropylethy
  • the reductive amination with a compound of formula XIIIb is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in an aprotic solvent, preferably tetrahydrofuran or dichloroethane, at a suitable temperature comprised between room temperature and the reflux temperature, preferably in a microwave reactor.
  • a reductive reagent preferably sodium triacetoxyborohydride
  • an aprotic solvent preferably tetrahydrofuran or dichloroethane
  • the transformation of a deprotected compound of formula XII, XVI and XVII to a compound of formula la-c can be effected in a two step procedure, involving acylation with an acid chloride of formula XIV following by reduction, as illustrated by the transformation of compound XII to give a compound of formula lb.
  • the acylation reaction of XII to give XV can be carried out using DIPEA in a suitable solvent such as dichloromethane at a suitable temperature, preferably room temperature.
  • the reduction reaction of XV to give IIb can be effected with a reducing agent such as lithium aluminium hydride, in a suitable solvent such as tetrahydrofuran, at a suitable temperature comprised between 0 °C and room temperature, preferably at 0 °C.
  • a reducing agent such as lithium aluminium hydride
  • a suitable solvent such as tetrahydrofuran
  • Example 1 1'-(2-Phenylethyl)-2,4-dihydro-1 H -spiro[isoquinoline-3,4'-piperidin]-1-one.
  • Acetic anhydride (0.22 mL, 2.28 mmol) was added to a solution of 1'-(2-phenylethyl)-1,4-dihydro-2 H -spiro[isoquinoline-3,4'-piperidine] (example 3, 140 mg, 0.46 mmol) and pyridine (0.18 mL, 2.28 mmol) in DCM (10 mL) and the mixture was stirred at reflux temperature overnight. The mixture was allowed to reach r.t., poured into H 2 O (20 mL), basified with NaOH (10% aqueous solution, 3 mL) and extracted with DCM (2x20 mL).
  • transfected HEK-293 membranes and [ 3 H](+)-pentazocine (Perkin Elmer, NET-1056), as the radioligand, were used.
  • the assay was carried out with 7 ⁇ g of membrane suspension, 5 nM of [ 3 H](+)-pentazocine in either absence or presence of either buffer or 10 ⁇ M Haloperidol for total and non-specific binding, respectively.
  • Binding buffer contained Tris-HCl 50 mM at pH 8. Plates were incubated at 37 °C for 120 minutes.
  • reaction mix was then transferred to MultiScreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris-HCL (pH7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail
  • this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the ⁇ 1 receptor it is a very preferred embodiment in which the compounds are selected which act as ligands of the ⁇ 1 receptor and especially compounds which have a binding expressed as K i which is preferably ⁇ 1000 nM, more preferably ⁇ 500 nM, even more preferably ⁇ 100 nM.

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Claims (15)

  1. Verbindung der allgemeinen Formel (I),
    Figure imgb0105
     worin
    m 0, 1, 2, 3, 4, 5 oder 6 ist;
    n 0, 1, 2, 3 oder 4 ist;
    p 1, 2, 3 oder 4 ist;
    R1 ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl, substituiertem oder unsubstituiertem C2-6 Alkinyl, substituiertem oder unsubstituiertem Cycloalkyl, substituiertem oder unsubstituiertem Heterocyclyl, -C(O)R6, -C(O)OR6,-C(O)NR6R6' und -S(O)2R6;
    wobei R6 und R6' unabhängig ausgewählt sind aus Wasserstoff, substituiertem
    oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl, substituiertem oder unsubstituiertem C2-6 Alkinyl, substituiertem oder unsubstituiertem Aryl oder substituiertem oder unsubstituiertem Alkylaryl, substituiertem oder unsubstituiertem Cycloalkyl oder substituiertem oder unsubstituiertem Alkylcycloalkyl und substituiertem oder unsubstituiertem Heterocyclyl oder substituiertem oder unsubstituiertem Alkylheterocylcyl;
    R2 ausgewählt ist aus substituiertem oder unsubstituiertem Cycloalkyl, substituiertem oder unsubstituiertem Aryl und substituiertem oder unsubstituiertem Heterocyclyl;
    wobei das Cycloalkyl, Aryl oder Heterocyclyl in R2, falls substituiert, substituiert ist mit einem oder mehreren Substituenten, ausgewählt aus Halogen, -R12, -OR12, -NO2, -NR12R12'", NR12C(O)R12', -S(O)2NR12R12',-NR12C(O)NR12'R12", -SR12, -S(O)R12, S(O)2R12, -CN, Halogenalkyl, Halogenalkoxy, -C(O)OR12, -C(O)NR12R12' und -NR12S(O)2NR12'R12";
    wobei das Cycloalkyl oder nichtaromatische Heterocyclyl in R2, falls substituiert, auch durch
    Figure imgb0106
    oder =O substituiert sein kann;
    wobei das Alkyl, Alkenyl oder Alkinyl in R2, falls substituiert, mit einem oder mehreren Substituent/en substituiert ist, ausgewählt aus -OR12, Halogen, -CN, Halogenalkyl, Halogenalkoxy, -SR12, -S(O)R12 und - S(O)2R12;
    wobei R12, R12' und R12" unabhängig ausgewählt sind aus Wasserstoff, unsubstituiertem C1-6 Alkyl und unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl;
    und wobei R12'" ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl und -Boc;
    X ausgewählt ist aus einer Bindung, -C(RxRx')- und-C(Rx)(OR7)-;
    Rx ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl, substituiertem oder unsubstituiertem C2-6 Alkinyl, -C(O)OR7, -C(O)NR7R7',-NR7C(O)R7' und -NR7R7'";
    Rx' ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl;
    R7, R7' und R7" unabhängig ausgewählt sind aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl und unsubstituiertem C2-6 Alkinyl;
    und wobei R7"' ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl und -Boc;
    R3 ausgewählt ist aus Wasserstoff, Halogen, -R9, -OR9, -NO2, -NR9R9'", -NR9C(O)R9', -NC(O)OR9, -NR9S(O)2R9',-S(O)2NR9R9', -NR9C(O)NR9'R9", -SR9, -S(O)R9, -S(O)2R9,-CN, Halogenalkyl, Halogenalkoxy, -C(O)OR9, -C(O)NR9R9', -NR9S(O)2NR9'R9" und -OC(O)R9;
    R3', R3" und R3'" unabhängig ausgewählt sind aus Wasserstoff, Halogen, -R9, -NO2, -NR9R9'", -NR9C(O)R9', -NC(O)OR9, -NR9S(O)2R9', -S(O)2NR9R9', -NR9C(O)NR9'R9",-SR9, -S(O)R9, -S(O)2R9, -CN, Halogenalkyl, Halogenalkoxy, -C(O)OR9, -C(O)NR9R9', -NR9S(O)2NR9'R9" und -OC(O)R9;
    wobei R9, R9' und R9" unabhängig ausgewählt sind aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl und unsubstituiertem C2-6 Alkinyl;
    und wobei R9'" ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl und -Boc;
    R4 ausgewählt ist aus Wasserstoff, -OR8, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl, substituiertem oder unsubstituiertem C2-6 Alkinyl,-C(O)OR8, -C(O)NR8R8', -NR8C(O)R8', -NR8R8'" und-NC(O)OR8';
    R4' ausgewählt ist aus Wasserstoff oder substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl;
    wobei R8, R8' und R8" unabhängig ausgewählt sind aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl und unsubstituiertem C2-6 Alkinyl;
    und wobei R8'" ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl,
    unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl und -Boc;
    alternativ R4 und R4' zusammen mit dem Kohlenstoff, an den sie gebunden sind, eine C=O-Gruppe bilden können;
    R5 und R5' unabhängig ausgewählt sind aus Wasserstoff oder substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl;
    wahlweise in Form eines der Stereoisomere, vorzugsweise Enantiomere oder Diastereomere, eines Racemats oder in Form eines Gemisches aus mindestens zwei der Stereoisomeren, vorzugsweise Enantiomeren und/oder Diastereomeren, in beliebigem Mischungsverhältnis oder eines entsprechenden Salzes davon oder eines entsprechenden Solvats davon,
    wobei die folgende Verbindung ausgenommen ist:
    Figure imgb0107
  2. Verbindung nach Anspruch 1, wobei
    m 0 oder 1 ist, n 0 oder 1 ist und p 1 ist.
  3. Verbindung nach einem der Ansprüche 1 oder 2, wobei
    R1 ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder
    unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl, oder -C(O)R6;
    und wobei R6 ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl.
  4. Verbindung nach einem der Ansprüche 1 bis 3, wobei
    R2 ausgewählt ist aus substituiertem oder unsubstituiertem Aryl und substituiertem oder unsubstituiertem Heterocyclyl.
  5. Verbindung nach einem der Ansprüche 1 bis 4, wobei
    X ausgewählt ist aus einer Bindung und -(CRxRx')-; und wobei
    Rx ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl;
    Rx' ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, substituiertem oder unsubstituiertem C2-6 Alkenyl und substituiertem oder unsubstituiertem C2-6 Alkinyl.
  6. Verbindung nach einem der Ansprüche 1 bis 5, wobei
    R3 ausgewählt ist aus Wasserstoff, Halogen, -R9, -OR9 und -NR9R9'"; und
    R3', R3" und R3'" unabhängig ausgewählt sind aus Wasserstoff, Halogen, -R9 und -NR9R9"';
    und wobei R9, R9' und R9" unabhängig ausgewählt sind aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl und unsubstituiertem C2-6 Alkinyl;
    R9'" ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl, unsubstituiertem C2-6 Alkinyl und -Boc.
  7. Verbindung nach einem der Ansprüche 1 bis 6, wobei
    R4 ausgewählt ist aus Wasserstoff, -OR8, substituiertem oder unsubstituiertem C1-6 Alkyl;
    R4' ausgewählt ist aus Wasserstoff oder substituiertem oder unsubstituiertem C1-6 Alkyl;
    und wobei R8 ausgewählt ist aus Wasserstoff, unsubstituiertem C1-6 Alkyl, unsubstituiertem C2-6 Alkenyl und unsubstituiertem C2-6 Alkinyl;
    oder
    R4 und R4' zusammen mit dem Kohlenstoff, an den sie gebunden sind, eine C=O-Gruppe bilden.
  8. Verbindung nach einem der Ansprüche 1 bis 7, wobei
    X eine Bindung ist.
  9. Verbindung nach den Ansprüchen 1 bis 8, wobei
    m 0 oder 1 ist; und
    n 0 oder 1 ist; und
    p 1 ist; und
    R1 ausgewählt ist aus Wasserstoff, substituiertem oder unsubstituiertem C1-6 Alkyl, vorzugsweise substituiertem oder unsubstituiertem Methyl, und-C(O)R6;
    und
    R2 ausgewählt ist aus substituiertem oder unsubstituiertem Aryl, vorzugsweise substituiertem oder unsubstituiertem Phenyl, und substituiertem oder unsubstituiertem Heterocyclyl, vorzugsweise substituiertem oder unsubstituiertem Morpholin;
    und
    X eine Bindung ist;
    und
    R3, R3', R3" und R3'" sämtlich Wasserstoff sind;
    und
    R4 und R4' beide Wasserstoff sind oder zusammen mit dem Kohlenstoff, an den sie gebunden sind, eine C=O-Gruppe bilden können;
    und
    R5 und R5' beide Wasserstoff sind;
    und
    R6 substituiertes oder unsubstituiertes C1-6 Alkyl ist, vorzugsweise substituiertes oder unsubstituiertes Methyl.
  10. Verbindung nach den Ansprüchen 1 bis 9, wobei die Verbindung ausgewählt ist aus
    • 1'-Phenethyl-2,4-dihydro-1H-spiro[isochinolin-3,4'-piperidin]-1-on,
    • 1'-Benzyl-2,4-dihydro-1H-spiro[isochinolin-3,4'-piperidin]-1-on,
    • 1'-Phenethyl-2,4-dihydro-1H-spiro[isochinolin-3,4'-piperidin],
    • 1'-Benzyl-2,4-dihydro-1H-spiro[isochinolin-3,4'-piperidin],
    • 1-(1'-Phenethyl-1H-spiro[isochinolin-3,4'-piperidin]-2(4H)-yl)ethanon,
    • 1'-Benzyl-2-methyl-2,4-dihydro-1H-spiro [isochinolin-3,4'-piperidin]
    und
    • 4-(2-(2-Methyl-2,4-dihydro-1H-spiro[isochinolin-3,4'-piperidin]-1'-yl)ethyl)morpholin.
  11. Verfahren zur Herstellung einer Verbindung der Formel (I), wie in einem der Ansprüche 1 bis 10 definiert, welches das Umsetzen einer Verbindung der Formel (Ib')
    Figure imgb0108
     mit einer Verbindung der Formel (Xla) in einer Alkylierungsreaktion, (Xlb) in einer reduktiven Aminierungsreaktion, (Xlc) in einer Acylierungsreaktion oder (Xld) in einer Acylierungsreaktion umfasst
    Figure imgb0109
     worin m, n, p, R1, R2, R3, R3', R3", R3"', R5, R5', R6 und X die Bedeutung wie in den vorhergehenden Ansprüchen definiert aufweisen, L eine Abgangsgruppe ist und W Chlor, Brom, -OH, -O-Methyl oder -O-Ethyl ist.
  12. Verwendung der Verbindungen der Formel IIa, IIb, III, IVa, IVb, Va, Vb, VIa, VIb, VIla, VIIb, VIII, Ia, IX, Ib, X, Ic, Xla, Xlb, Xlc, Xld, XII, Xllla, XIIIb, XIV, XV, XVI, XVII, XVII', Ib', X', I', IX' oder lb' zur Herstellung einer Verbindung der Formel (I), wie in einem der Ansprüche 1 bis 10 definiert,
    Figure imgb0110
    Figure imgb0111
    Figure imgb0112
    Figure imgb0113
    Figure imgb0114
    Figure imgb0115
    Figure imgb0116
    Figure imgb0117
     worin m, n, p, R1, R2, R3, R3', R3", R3"', R5, R5', R6 und X die in den vorhergehenden Ansprüchen definierte Bedeutung aufweisen, L eine Abgangsgruppe ist, W Chlor, Brom, -OH, -O-Methyl oder -O-Ethyl ist, PG eine Schutzgruppe ist und Y
    Figure imgb0118
  13. Pharmazeutische Zusammensetzung, die eine Verbindung der Formel (I), wie in einem der Ansprüche 1 bis 10 definiert, oder ein pharmazeutisch verträgliches Salz davon und einen pharmazeutisch verträglichen Träger, Adjuvans oder Vehikel umfaßt.
  14. Verbindung der Formel (I) nach einem der Ansprüche 1 bis 10 zur Verwendung als Arzneimittel.
  15. Verbindung der Formel (I) nach einem der Ansprüche 1 bis 10 zur Verwendung als Arzneimittel zur Behandlung von einer mit Sigma-1 (σ1) Rezeptoren in Zusammenhang stehenden Erkrankung;
    oder zur Verwendung als Arzneimittel zur Behandlung von Schmerz, insbesondere von mittlerem bis starkem Schmerz, viszeralem Schmerz, chronischem Schmerz, Krebsschmerz, Migräne, entzündlichem Schmerz, akutem Schmerz oder neuropathischem Schmerz, Allodynie oder Hyperalgesie.
EP16719214.5A 2015-04-28 2016-04-27 Spiro-isochinolin-3,4'-piperidin-verbindungen mit aktivität gegen schmerzen Not-in-force EP3288941B1 (de)

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US11485725B2 (en) 2017-12-15 2022-11-01 Auransa Inc. Derivatives of piperlongumine and uses thereof
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